CA2107061A1 - Piperidine derivatives, their preparation and their application in therapy - Google Patents
Piperidine derivatives, their preparation and their application in therapyInfo
- Publication number
- CA2107061A1 CA2107061A1 CA002107061A CA2107061A CA2107061A1 CA 2107061 A1 CA2107061 A1 CA 2107061A1 CA 002107061 A CA002107061 A CA 002107061A CA 2107061 A CA2107061 A CA 2107061A CA 2107061 A1 CA2107061 A1 CA 2107061A1
- Authority
- CA
- Canada
- Prior art keywords
- disorder
- compound
- formula
- alkyl
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
ABSTRACT
A compound which is a piperidine derivative of formula (I) (I) in which R represents hydrogen, or unbranched or branched C1-C6 alkyl group; and Ar represents phenyl optionally substituted with one or more radicals selected from the halogens, amino, C1-C2 alkoxy and (C3-C6)cycloalkyl(C1-C2)alkoxy, or a heteroaryl group;
or a pharmaceutically acceptable acid addition salt thereof;
provided that when R is hydrogen Ar is not phenyl or 4-chlorophenyl.
The compounds are useful in therapy as ligands for 5-HT3 and 5-HT4 receptors.
A compound which is a piperidine derivative of formula (I) (I) in which R represents hydrogen, or unbranched or branched C1-C6 alkyl group; and Ar represents phenyl optionally substituted with one or more radicals selected from the halogens, amino, C1-C2 alkoxy and (C3-C6)cycloalkyl(C1-C2)alkoxy, or a heteroaryl group;
or a pharmaceutically acceptable acid addition salt thereof;
provided that when R is hydrogen Ar is not phenyl or 4-chlorophenyl.
The compounds are useful in therapy as ligands for 5-HT3 and 5-HT4 receptors.
Description
21 07~6~
~ he invention relate~ to piperidine derivatives, to their preparation and their application in therapy.
According to the invention there i~ provided a co~pound which i~ a piperidine derivative of formula (I) ~ N~
in which R represents hydrogen, or unbranched or branched C1-C6 alkyl; and Ar represents phenyl optionally ~ubstituted with one or more radicals selected from the halogens, amino, C1-C2 alkoxy and (C3-C6)cycloalkyl(Cl-C2)alkoxy, or a heteroaryl group; -or a pharmaceutically acceptable acid addition ~alt thereof;
provided that when R is hydrogen Ar i8 not phenyl or 4-chlorophenyl.
When Ar repre~ent~ ~ubst~tuted phenyl, the number of radicals on the phenyl group is ~rom 0 to 5, preferably 2 or 3~
Pre~erred compounds of the invention ~r~ ones in which Ar r~present~ phenyl optionally substituted .
' .
with one or more radicals selected from chlorine, amino, methoxy and cyclopropylmethoxy; i~idazo[l,2-a~pyridin-2-yl; 3-indolyl; or 3-indazolyl optionally ~ubstituted at position 1 with a radical selected from S C~-C2 alkyl and aryl(C1-C2)al~yl and at position 5 w$th a radical selected from hydrogen, the halogens and C1-C2 alkyl.
Particularly preferred compounds are those in which Ar represents 3-indazolyl optionally substituted at position 1 with a radical selected from C1-C2 alkyl ~nd aryl(C1-C2)alkyl and at position 5 with a radical selected from hydrogen, the halogens and Cl-C2 alkyl.
The compounds according to the invention can be in the form of free bases or of addition 6alts with pharmaceutically acceptable acids. The compounds whose formula i5 a mesomeric form of formula (I) are included in the invention.
EP-A-0 494 010 describes compounds of formula (I) in which R i6 ~ydrogen and Ar is phenyl optionally substituted at the para-position with chlorine.
According to the invention, the compounds of formula (I) ~ay be prepared according to the process illu~trated in Scheme 1 below: -SchQme 1 ~NH ~ ~ --~ ~
q~ .
lr 1) ~111) ) ,, ' , , ' , ' ' ,: , ' -.
2107~6~
a compound of formula (II) in which Ar i6 a~
defined above ~nd X represent~ ~ halogen, for example chlorine, or hydroxyl, i6 reacted with a piperidine derivative of formula (III) in which R i5 a8 defined above. The compound of formula ~I) thereby produced may be converted into a pharmaceutically acceptable acid addition ~alt ~n ~ known ~anner.
~ he ~tarting compounds are commercially available or are described in the literature, or may be prepared according to methods which are described therein or which are known to a person skilled in the art.
lH-Indazole-3-carboxylic acid is described in J. Amer. ~hem. Soc., 1952, 2009.
4-Amino-5-chloro-2-~cyclopropylmethoxy)-benzoic acid is described in GB-A-1 507 462, GB-A-l 088 581 and GB-A-101 978.
4-(lH-Imidazol-4-yl~piperidine is described in Arch. Pharmaz., (Weinheim. Ger.) 1973, 306(12), 934-42 and in EP-A-0 197 840.
4-(5-Methyl-lH-imidazol-4-yl)pyridine is described in J. ~ed. Chem., 1986, 2~, 2154-63.
The Examples which follow illustrate in detail the preparation of compounds according to the invention. The ~tructure of the compounds obtained were confirmed by microanaly~es and IR and NMR 6pectra.
- ~ .......
. :. :-..
- - - ~ . : . , . :
.
, .
, 2107~6 ~
1-(3,5-Dichlorobenzoyl)-4-(lH-i~idazol-4-yl)piperid~ne fu~arate 0.469 g (2.5 mmol) of 4-(lH-imidazol-4-yl)-S piperidine ~onohydrochloride i6 di6~01ved in 5 ml of 1 N ~odium hydroxide at O-C. 0.524 g (2.5 ~mol) of 3,5-dichlorobenzoyl chloride i~ then added and the ~ixturo iB stirred at O-C for 15 minutes. The precipitate obtained i~ filtered off, wa~hed with 1 N
60dium hydroxide and then with water and dried. The re~idue i6 recrystallized in ethanol.
0.4 g of product are obtained.
Melting point ~ 240-242 C
The fumarate i6 prepared by dissolving the base in ethanol and then adding one eguivalent of fumaric acid. The fumarate i6 recrystallized in a ~ix*ure of i~opropanol and ethanol.
Melting point ~ 178-183-C
Exam~le 2 `
4-(lH-Imidazol-4-yl)-1-[(lH-indol-3-yl)carbonyl]-piperidine fumarate 0.81 Dl (5.82 ~mol) of triethylamine i~ added to a cutpen~ion of 0.48 g (3 Dmol) of lN-indole-3-CarbOXyliC acid and 0.453 g (3 ~mol) of 4-(lN-i~idazol-4-yl)piperidine in 10 ~1 of dichloromethane, at room temperature and under argon.
1.29 ~1 (6 ~mol) of diphenylpho~phoryl azide are added and th- ~ixturo i- tirred for 20 hours. Tho r-action ~ . .
2107~6 1 medium iB xtracted with ethyl acetate in an acid medium. The aqueous phase i~ recovered, alkalinized with potassium carbonate ~olution and extracted with othyl acetate. The organic phase ~ 6 recovered ~nd washed with water and then with caturated ~odium chloride ~olution. It io dried over magnesium ~ulphate.
The residue obtained is purified by chromatography on a column of silica gel, eluting with a dichloromethane/
~ethanol ~90:10) mixture. The pure fractions are evaporated and 0.27 g of product i6 collected.
To prepare the fumarate, the base is taken up with ethanol and one equivalent of fumaric acid i8 added. After recrystallization in a mixture of ethanol and i~opropyl ether, the product obtained in the form of a hemifumarate i8 filtered off and dried.
0.3 g of product is obtained.
Melting point ~ 250~C (dec) Yield G 28 %
ExamDle 3 l-t~lH-Indazol-3-yl)carbonyl]-4-(5-methyl-lH-~midazol-4-yl)piperidine fumarate In a 100-ml round-bottomed fla6k, 1.35 g (8.15 mmol) of ~-(5-methyl-lH-imidazol-4-yl)piperidine are placed in 15 ml of dichloromethane and 4 ml of diemthylfor-amide. 1.32 g (8.15 mmol) of lH-indazole-3-carboxylic acid and 2.2 ml of triethylamine are added.~he aixture i~ let stirring for 5 minutes. 3.5 ml of dlphenylpho6phoryl azide are added and the mixture $s l-ft ~tirring for 72 hour~. Ethyl acetate i6 added and - - : .. . . . . ................................. . .
' . ' .: '' ',"' '' ' ' ' ,'' -" .'~' ~ '; ' " " ', ' 2 1 ~ 7 0 6 1 the ~lxture $6 extr~cted 3 tloes with 2 N hydrochloric acid. The agueous phase iB recovered and alkalinized with ~odium carbonate ~olution. It lo extr~cted 3 times with thyl acetate and the organic phase i~ collected, dried and evapor~ted to dryne~s. The residue $B
purified by chroma~ography on ~ column of 6ilica gel, eluting with a dichloromethane/methanol/ammonia 601ution (90:10:1) mixture.
1 g of product i~ recovered in the form of the pure base.
The fumarate is prepared as described in Example 1.
Melting point = 213-215-C Yield - 32 % -The table which follows illustrates the - -chemical structures ~nd physical properties of a few compounds according to the invention.
Legend to the table in the ~M.p. (-C~ column of the table (dec) denote6 decomposition in the ~Salt~ column of the table (x:y) denotes x mol of acid for y mol of ba~e, the absence of any comment ~eans that the compound ~8 in the ~tate of the base, chlor. represents the hydrochloride fum. repre~ents the fumarate ~ethanesulph. represents the methanesulphonate .... -. : . :
2107~ l llable NH
N~
~r ::
No . Ar M . p . ( C) Salt .' -N ~ 7a-1 3 ¦ ~u=. (1:2~ 1 ~X I ' '' :~ S ~I~L
: .
~ - . .. .
..... , .. . ~ ~ .. ... . ..... . .... ..... .. .. ... . . . ~. .. . . " .. . ... .. ..
, ! ' .. " ' . ', ' ' '.',, ' ' ' ' '' '.' ''' ,.'' ` ~.~.' ' :' . . ',' .,, ,. ', ' `
2107~61 No. ¦ R ¦ Ar ¦~M P ( C) ¦ Salt ~ _11 ~ 1~5(~-) _ _ .
6 -H ~220 (dec) fum. (1:2) . _ , 7 -CH3 ~175-180 fum. (1:1) _ . .- .
8 -H bJ~Nh210 (dec) fum. (1:2) . .
'I ' , ' ' , ' 21~7061 No. ~= M.p. (-C) Salt 9 -CH3 ~N~ 202 _ -CH3 ~Nh 213-215 fu~. (1:2) ~N methanesulph. - ~
11 --CH3 ~NH 235--237 (1:1) : . :
. ~.' 12~ (CH2) 2CH3 I~N 217-222 fum. (1: 1) ~ ~ ¦219-241 ruL. ;~
. L _ . . :
210706~.
No. Ar M.p. (-C) Salt -H ~ 185-192 funl. (1:1) ._ H~
16 -CH3 ~ 186-192 fum . ( 1 :1) 17 _~ ~ ~ ~
18 -CH~ ~H 206-212 fum. (1:1) ., .
c,~ , , 19 -(CH2)3CH3bJI--"i. 30-135 chlor. (1:1) . -, .. . - , . .. ,. . .. , ~ . - . ~ .. .
-.
: . : . `
210706~
No. R Ar ~.p. (-C) Salt ~ ¦ lal ~ -21CH2 ~IN ~ 182 184 22_~ ~ 172~175 fum. (1:1) 23 -(CH2)3CH3 u~ 217-220 _ .. . . . .. .
, , . . . . :
210706~
No. R Ar M.p. ( C) ¦ Salt 25 CH3 ~/R 218-225 fum. (171) _ . .
2 6 ~ (CH2) ~CH3 a~cN~3 > 250 _ ~27 ~ 165-167 fw~
.
. : . ,: : , , . . - ~ : , 2l07a~l T~e compounds of the lnvention were ~ubjected to pharm~cological testC whioh ~howed their value ~6 therapeutically active ~ubstance6.
Thu6, they were te6ted for their effects on the accummulation of cAMP in a primary culture preparation of neuron6 of mouAe embryo colliculi according to the technique described by Dumuis et al~, Mol. Pharmacol., ~, 880-887, 1988~ Thi~ ~ccummulation reflecte adenylcyclase activity to which the type 5-HT~
~erotoninergic receptors are coupled positively.
Colliculi are removed from 14- to 15-day-old mouse embryos. The neurons are ~eparated mechanically and cultured, in 12-well CostarT~ dishes on the basis of 106 cells per well, in a DNEM/F12~ nutrient medium with 6upplement~ but without ~erum. The cultures are ~aintained at 37-C in a humidified atmosphere (5 % C02/
95 % air). ~ -Six days after culturing i5 started, the cells are ~ncubated for 2 hours ~n the culture medium de~cribed above in the pre~enc¢ of 0.1 nmol of triti~ted aden~ne (6peciic acti~ity 20 Ci/mmol) per well. The cell~ are wa~hed with the culture medium and ~ ~econd ~ncubation i6 carried out in the culture Dedium in the prefience of i~obutylmethylxanthine ~0.75 ~M), for~kolin tO.l ~M) and test product~ ~t different concentrations, in ~ final volume of 1 ml per well. After 10 minute6 of incubation, ~he re~ction is ~topped by a~pirating the medium and adding 1 ml of 5 %
, .. , , .. , ' , . .
,' .. ..
210706~.
trichloroacetic acid. The neurons are detached, homogenized using ultrasound and centrifuged at 8000 g for 2.5 minute6. The ~upernatant i~ collected and 100 ~1 of a solution containing cAMP ~5 mM) and ATP
(5 ~M) are added. The tritiated ATP and cAMP formed are ~eparated by pas~age through DOWEXT~ AG50WX8 resin ~nd then through alumina.
The result6 were expres~ed as % t~H~-cAMP/
[~H~-ATP
The EC50 and IC50 values represent, respectively, the concentrations which produce one half of the maximal stimulation and of the maximal inhibition.
The compounds of the invention which are most active in this test are characterized by ICso values of between 1 and 10 ~M.
The compounds of the invention were also tested in vivo for their effect on S-HTP-induced diarrhoea in mice according to the technique described by ~arrick et al., J. Pharm. Pharmacol., 33, 675-676, 1981. Male CD1 mice weighing 25-30 g and fa~ted for 18 ~our~ are ufied. The compound6 or t~e vehicle i~are admini6tered 20 minutes (intraperitoneal route) or 60 ~inutes (oral route) before the $ntraperitoneal in~ection of 5-HTP at a do~e of 25 mg/kg. The animal~
are placed in individual cage~ and are observed for 3 hour~, noting the number of animal~ having diarrhoea 30 ~inute~, 1 hour, 2 hours and 3 hour6 after the ;; . . ..
. . - . . . : .
.. : : : . . -. .. : : .
, .
21~7061 administration of 5-HTP.
m e re~ults are expressed as ~ percentage of animal~ protected by the pretreatment ln comparison to the control animals which have received the vehicle as a pretreatment.
The compounds of the lnvention wh~ch are most ~ctive in this test lnhibit S-HTP-induced diarrhoea bfter a dose of 0.002 ~g/kg ad~ini~tered intraperitoneally or 0.1 mg/kg admini~tered orally.
$he compounds ~ccording to the inYention were also te~ted for their inhibitory effectc on the binding of 13H]quipazine to the type 5-HT3 serotoninergic receptors pre6ent in the rat cerebral cortex, according to a variant of the method de~cribed by Milburn and Peroutka (J. Neurochem., S2, 1787-1792, 1989).
Male Sprague-Dawley rats weighing 150 to 200 g ~re used in all the tests. Their cerebral cortex i~ removed and homogenized in 20 volumes ~weight/volume) of 25 DM Hepes buffer or of 25 mM ~epes buffer containlng sodium chloride (180 ~M), calcium ohloride (2.5 ~M), potassium chloride (5 mM) and ~agne6ium chloride (1.2 ~M) (pH 7.4) using a Polytro~
~ill. After ~entrifugation of the suspension for 10 ~inute~ ~t 45,000 x g, the pe~let i6 resuspended ~n the initial volume of buffer, where appropriate containinq 0.05% of Triton X-lOOT~, ~nd a first incubat~on is performed ~or 39 ~inute~ at 37-C. Two further oentri~ugations are then performed aB descrlbed above, . . . . .. . . ., - . .
. . .
. .
: ~' . .' :, . . .
2107~6:~
~nd the final pellet ie taken up in 11.7 volumes of 25 aM Hepe6 buffer, pH 7.4.
The binding of t~H]quipazine (51.6-69.8 Ci/
smol, New England Nuclear, Boston, Ma, USA) iB
deter~ned by incubating 150 ~l of the Dembrane ~uspension with the radioligand (0.8 nM) in a ~inal volume of 1 ~l for 30 minutes at 25-C, in the absence or presence of the compound under 6tudy. Incubation takes place in the presence of 0.1 ~M paroxetine ~nd 1 ~M ketanserin. Non-specific binding i~ determined in the presence of 1 ~M ondansetron. After incubation, the test mixture is diluted with 5 ~l of ice-cold 50 mM
Tri6-HCl buffer (pH 7.4 8t 0 ' C) . The membranes are collected by filtration on Whatman GF/B~ filters pretreated with 0.05% of polyethylenimine, and washed with three volumes of 5 ml of ice-cold 50 mM Tris-HCl buffer.
The radioactivity retained on the filters is ~easured by liguid ~cintillation ~pectrometry at an efficiency of 50 to 60%.
The re6ultE are ~xpressed ~s the concentration (IC5o) of the compound under study which inhibits 50% of the binding of t~H]guip~zine, deter~ined by ~ graphic or ~athematical method. The compoundc of the invention which ~re ~o~t active in this test are characterized by I~o v~lues kelow 1 nM ~lO ~M)~
~ he r~ults of the ~iological te~ts show that the compounds of the inv~ntion are ligands for types - . .
. . ,., . , .
..
. . .
210706~
5-HT3 and 5-HT~ serotoninergic receptors.
They ~ay hence be used for the treatment and prevention of d~orders in which 5-HT3 ~nd 5-HT~
receptors are lnvolved, ~uch as nausea and ~omit$ng, S for xa~ple following antitumour treatment or the administration of ~n ~naeqthetic; disorders of the central nervous ~y~tem ~uch a6 schizophrenia, mania, anxiety ~nd depression: di~orders of cognition such ~s senile dementia or Alzheimer's presenile dementia;
dyskine~ia, pain, migraine and headache; disorders ~ssociated with alcohol or drug dependence or withdrawal; disorders of gastro intestinal function such ~s dyspepsia, peptic ulcer, heartburn, ~latulence:
disorders of the cardiovascular system and respiratory disorders.
They may also be used for the treatment and prevention of disorders 6uch as diarrhoea, irritable colon, oesophageal reflux, inte tinal motor disorders, disorderc of intestinal secretion, cystic fibrosic of the pancreas, carcinoid ~yndrome ~nd $ncontinence.
For thi~ purpo~e, they ~ay be presented in ~11 form6 ~uitable for oral or parenteral admini~tration, 6uch as tablet6, dragees, capsules including hard gel~tin capsules, ~uspensions or olution~ to be swallowed or injected, and the like, in combin~tion with suitable excipients, ~nd in doses that enable 0.005 to 10 ~g to be administQred 1 to 4 time6 a day.
- . . . .
: . . .. . .
~ he invention relate~ to piperidine derivatives, to their preparation and their application in therapy.
According to the invention there i~ provided a co~pound which i~ a piperidine derivative of formula (I) ~ N~
in which R represents hydrogen, or unbranched or branched C1-C6 alkyl; and Ar represents phenyl optionally ~ubstituted with one or more radicals selected from the halogens, amino, C1-C2 alkoxy and (C3-C6)cycloalkyl(Cl-C2)alkoxy, or a heteroaryl group; -or a pharmaceutically acceptable acid addition ~alt thereof;
provided that when R is hydrogen Ar i8 not phenyl or 4-chlorophenyl.
When Ar repre~ent~ ~ubst~tuted phenyl, the number of radicals on the phenyl group is ~rom 0 to 5, preferably 2 or 3~
Pre~erred compounds of the invention ~r~ ones in which Ar r~present~ phenyl optionally substituted .
' .
with one or more radicals selected from chlorine, amino, methoxy and cyclopropylmethoxy; i~idazo[l,2-a~pyridin-2-yl; 3-indolyl; or 3-indazolyl optionally ~ubstituted at position 1 with a radical selected from S C~-C2 alkyl and aryl(C1-C2)al~yl and at position 5 w$th a radical selected from hydrogen, the halogens and C1-C2 alkyl.
Particularly preferred compounds are those in which Ar represents 3-indazolyl optionally substituted at position 1 with a radical selected from C1-C2 alkyl ~nd aryl(C1-C2)alkyl and at position 5 with a radical selected from hydrogen, the halogens and Cl-C2 alkyl.
The compounds according to the invention can be in the form of free bases or of addition 6alts with pharmaceutically acceptable acids. The compounds whose formula i5 a mesomeric form of formula (I) are included in the invention.
EP-A-0 494 010 describes compounds of formula (I) in which R i6 ~ydrogen and Ar is phenyl optionally substituted at the para-position with chlorine.
According to the invention, the compounds of formula (I) ~ay be prepared according to the process illu~trated in Scheme 1 below: -SchQme 1 ~NH ~ ~ --~ ~
q~ .
lr 1) ~111) ) ,, ' , , ' , ' ' ,: , ' -.
2107~6~
a compound of formula (II) in which Ar i6 a~
defined above ~nd X represent~ ~ halogen, for example chlorine, or hydroxyl, i6 reacted with a piperidine derivative of formula (III) in which R i5 a8 defined above. The compound of formula ~I) thereby produced may be converted into a pharmaceutically acceptable acid addition ~alt ~n ~ known ~anner.
~ he ~tarting compounds are commercially available or are described in the literature, or may be prepared according to methods which are described therein or which are known to a person skilled in the art.
lH-Indazole-3-carboxylic acid is described in J. Amer. ~hem. Soc., 1952, 2009.
4-Amino-5-chloro-2-~cyclopropylmethoxy)-benzoic acid is described in GB-A-1 507 462, GB-A-l 088 581 and GB-A-101 978.
4-(lH-Imidazol-4-yl~piperidine is described in Arch. Pharmaz., (Weinheim. Ger.) 1973, 306(12), 934-42 and in EP-A-0 197 840.
4-(5-Methyl-lH-imidazol-4-yl)pyridine is described in J. ~ed. Chem., 1986, 2~, 2154-63.
The Examples which follow illustrate in detail the preparation of compounds according to the invention. The ~tructure of the compounds obtained were confirmed by microanaly~es and IR and NMR 6pectra.
- ~ .......
. :. :-..
- - - ~ . : . , . :
.
, .
, 2107~6 ~
1-(3,5-Dichlorobenzoyl)-4-(lH-i~idazol-4-yl)piperid~ne fu~arate 0.469 g (2.5 mmol) of 4-(lH-imidazol-4-yl)-S piperidine ~onohydrochloride i6 di6~01ved in 5 ml of 1 N ~odium hydroxide at O-C. 0.524 g (2.5 ~mol) of 3,5-dichlorobenzoyl chloride i~ then added and the ~ixturo iB stirred at O-C for 15 minutes. The precipitate obtained i~ filtered off, wa~hed with 1 N
60dium hydroxide and then with water and dried. The re~idue i6 recrystallized in ethanol.
0.4 g of product are obtained.
Melting point ~ 240-242 C
The fumarate i6 prepared by dissolving the base in ethanol and then adding one eguivalent of fumaric acid. The fumarate i6 recrystallized in a ~ix*ure of i~opropanol and ethanol.
Melting point ~ 178-183-C
Exam~le 2 `
4-(lH-Imidazol-4-yl)-1-[(lH-indol-3-yl)carbonyl]-piperidine fumarate 0.81 Dl (5.82 ~mol) of triethylamine i~ added to a cutpen~ion of 0.48 g (3 Dmol) of lN-indole-3-CarbOXyliC acid and 0.453 g (3 ~mol) of 4-(lN-i~idazol-4-yl)piperidine in 10 ~1 of dichloromethane, at room temperature and under argon.
1.29 ~1 (6 ~mol) of diphenylpho~phoryl azide are added and th- ~ixturo i- tirred for 20 hours. Tho r-action ~ . .
2107~6 1 medium iB xtracted with ethyl acetate in an acid medium. The aqueous phase i~ recovered, alkalinized with potassium carbonate ~olution and extracted with othyl acetate. The organic phase ~ 6 recovered ~nd washed with water and then with caturated ~odium chloride ~olution. It io dried over magnesium ~ulphate.
The residue obtained is purified by chromatography on a column of silica gel, eluting with a dichloromethane/
~ethanol ~90:10) mixture. The pure fractions are evaporated and 0.27 g of product i6 collected.
To prepare the fumarate, the base is taken up with ethanol and one equivalent of fumaric acid i8 added. After recrystallization in a mixture of ethanol and i~opropyl ether, the product obtained in the form of a hemifumarate i8 filtered off and dried.
0.3 g of product is obtained.
Melting point ~ 250~C (dec) Yield G 28 %
ExamDle 3 l-t~lH-Indazol-3-yl)carbonyl]-4-(5-methyl-lH-~midazol-4-yl)piperidine fumarate In a 100-ml round-bottomed fla6k, 1.35 g (8.15 mmol) of ~-(5-methyl-lH-imidazol-4-yl)piperidine are placed in 15 ml of dichloromethane and 4 ml of diemthylfor-amide. 1.32 g (8.15 mmol) of lH-indazole-3-carboxylic acid and 2.2 ml of triethylamine are added.~he aixture i~ let stirring for 5 minutes. 3.5 ml of dlphenylpho6phoryl azide are added and the mixture $s l-ft ~tirring for 72 hour~. Ethyl acetate i6 added and - - : .. . . . . ................................. . .
' . ' .: '' ',"' '' ' ' ' ,'' -" .'~' ~ '; ' " " ', ' 2 1 ~ 7 0 6 1 the ~lxture $6 extr~cted 3 tloes with 2 N hydrochloric acid. The agueous phase iB recovered and alkalinized with ~odium carbonate ~olution. It lo extr~cted 3 times with thyl acetate and the organic phase i~ collected, dried and evapor~ted to dryne~s. The residue $B
purified by chroma~ography on ~ column of 6ilica gel, eluting with a dichloromethane/methanol/ammonia 601ution (90:10:1) mixture.
1 g of product i~ recovered in the form of the pure base.
The fumarate is prepared as described in Example 1.
Melting point = 213-215-C Yield - 32 % -The table which follows illustrates the - -chemical structures ~nd physical properties of a few compounds according to the invention.
Legend to the table in the ~M.p. (-C~ column of the table (dec) denote6 decomposition in the ~Salt~ column of the table (x:y) denotes x mol of acid for y mol of ba~e, the absence of any comment ~eans that the compound ~8 in the ~tate of the base, chlor. represents the hydrochloride fum. repre~ents the fumarate ~ethanesulph. represents the methanesulphonate .... -. : . :
2107~ l llable NH
N~
~r ::
No . Ar M . p . ( C) Salt .' -N ~ 7a-1 3 ¦ ~u=. (1:2~ 1 ~X I ' '' :~ S ~I~L
: .
~ - . .. .
..... , .. . ~ ~ .. ... . ..... . .... ..... .. .. ... . . . ~. .. . . " .. . ... .. ..
, ! ' .. " ' . ', ' ' '.',, ' ' ' ' '' '.' ''' ,.'' ` ~.~.' ' :' . . ',' .,, ,. ', ' `
2107~61 No. ¦ R ¦ Ar ¦~M P ( C) ¦ Salt ~ _11 ~ 1~5(~-) _ _ .
6 -H ~220 (dec) fum. (1:2) . _ , 7 -CH3 ~175-180 fum. (1:1) _ . .- .
8 -H bJ~Nh210 (dec) fum. (1:2) . .
'I ' , ' ' , ' 21~7061 No. ~= M.p. (-C) Salt 9 -CH3 ~N~ 202 _ -CH3 ~Nh 213-215 fu~. (1:2) ~N methanesulph. - ~
11 --CH3 ~NH 235--237 (1:1) : . :
. ~.' 12~ (CH2) 2CH3 I~N 217-222 fum. (1: 1) ~ ~ ¦219-241 ruL. ;~
. L _ . . :
210706~.
No. Ar M.p. (-C) Salt -H ~ 185-192 funl. (1:1) ._ H~
16 -CH3 ~ 186-192 fum . ( 1 :1) 17 _~ ~ ~ ~
18 -CH~ ~H 206-212 fum. (1:1) ., .
c,~ , , 19 -(CH2)3CH3bJI--"i. 30-135 chlor. (1:1) . -, .. . - , . .. ,. . .. , ~ . - . ~ .. .
-.
: . : . `
210706~
No. R Ar ~.p. (-C) Salt ~ ¦ lal ~ -21CH2 ~IN ~ 182 184 22_~ ~ 172~175 fum. (1:1) 23 -(CH2)3CH3 u~ 217-220 _ .. . . . .. .
, , . . . . :
210706~
No. R Ar M.p. ( C) ¦ Salt 25 CH3 ~/R 218-225 fum. (171) _ . .
2 6 ~ (CH2) ~CH3 a~cN~3 > 250 _ ~27 ~ 165-167 fw~
.
. : . ,: : , , . . - ~ : , 2l07a~l T~e compounds of the lnvention were ~ubjected to pharm~cological testC whioh ~howed their value ~6 therapeutically active ~ubstance6.
Thu6, they were te6ted for their effects on the accummulation of cAMP in a primary culture preparation of neuron6 of mouAe embryo colliculi according to the technique described by Dumuis et al~, Mol. Pharmacol., ~, 880-887, 1988~ Thi~ ~ccummulation reflecte adenylcyclase activity to which the type 5-HT~
~erotoninergic receptors are coupled positively.
Colliculi are removed from 14- to 15-day-old mouse embryos. The neurons are ~eparated mechanically and cultured, in 12-well CostarT~ dishes on the basis of 106 cells per well, in a DNEM/F12~ nutrient medium with 6upplement~ but without ~erum. The cultures are ~aintained at 37-C in a humidified atmosphere (5 % C02/
95 % air). ~ -Six days after culturing i5 started, the cells are ~ncubated for 2 hours ~n the culture medium de~cribed above in the pre~enc¢ of 0.1 nmol of triti~ted aden~ne (6peciic acti~ity 20 Ci/mmol) per well. The cell~ are wa~hed with the culture medium and ~ ~econd ~ncubation i6 carried out in the culture Dedium in the prefience of i~obutylmethylxanthine ~0.75 ~M), for~kolin tO.l ~M) and test product~ ~t different concentrations, in ~ final volume of 1 ml per well. After 10 minute6 of incubation, ~he re~ction is ~topped by a~pirating the medium and adding 1 ml of 5 %
, .. , , .. , ' , . .
,' .. ..
210706~.
trichloroacetic acid. The neurons are detached, homogenized using ultrasound and centrifuged at 8000 g for 2.5 minute6. The ~upernatant i~ collected and 100 ~1 of a solution containing cAMP ~5 mM) and ATP
(5 ~M) are added. The tritiated ATP and cAMP formed are ~eparated by pas~age through DOWEXT~ AG50WX8 resin ~nd then through alumina.
The result6 were expres~ed as % t~H~-cAMP/
[~H~-ATP
The EC50 and IC50 values represent, respectively, the concentrations which produce one half of the maximal stimulation and of the maximal inhibition.
The compounds of the invention which are most active in this test are characterized by ICso values of between 1 and 10 ~M.
The compounds of the invention were also tested in vivo for their effect on S-HTP-induced diarrhoea in mice according to the technique described by ~arrick et al., J. Pharm. Pharmacol., 33, 675-676, 1981. Male CD1 mice weighing 25-30 g and fa~ted for 18 ~our~ are ufied. The compound6 or t~e vehicle i~are admini6tered 20 minutes (intraperitoneal route) or 60 ~inutes (oral route) before the $ntraperitoneal in~ection of 5-HTP at a do~e of 25 mg/kg. The animal~
are placed in individual cage~ and are observed for 3 hour~, noting the number of animal~ having diarrhoea 30 ~inute~, 1 hour, 2 hours and 3 hour6 after the ;; . . ..
. . - . . . : .
.. : : : . . -. .. : : .
, .
21~7061 administration of 5-HTP.
m e re~ults are expressed as ~ percentage of animal~ protected by the pretreatment ln comparison to the control animals which have received the vehicle as a pretreatment.
The compounds of the lnvention wh~ch are most ~ctive in this test lnhibit S-HTP-induced diarrhoea bfter a dose of 0.002 ~g/kg ad~ini~tered intraperitoneally or 0.1 mg/kg admini~tered orally.
$he compounds ~ccording to the inYention were also te~ted for their inhibitory effectc on the binding of 13H]quipazine to the type 5-HT3 serotoninergic receptors pre6ent in the rat cerebral cortex, according to a variant of the method de~cribed by Milburn and Peroutka (J. Neurochem., S2, 1787-1792, 1989).
Male Sprague-Dawley rats weighing 150 to 200 g ~re used in all the tests. Their cerebral cortex i~ removed and homogenized in 20 volumes ~weight/volume) of 25 DM Hepes buffer or of 25 mM ~epes buffer containlng sodium chloride (180 ~M), calcium ohloride (2.5 ~M), potassium chloride (5 mM) and ~agne6ium chloride (1.2 ~M) (pH 7.4) using a Polytro~
~ill. After ~entrifugation of the suspension for 10 ~inute~ ~t 45,000 x g, the pe~let i6 resuspended ~n the initial volume of buffer, where appropriate containinq 0.05% of Triton X-lOOT~, ~nd a first incubat~on is performed ~or 39 ~inute~ at 37-C. Two further oentri~ugations are then performed aB descrlbed above, . . . . .. . . ., - . .
. . .
. .
: ~' . .' :, . . .
2107~6:~
~nd the final pellet ie taken up in 11.7 volumes of 25 aM Hepe6 buffer, pH 7.4.
The binding of t~H]quipazine (51.6-69.8 Ci/
smol, New England Nuclear, Boston, Ma, USA) iB
deter~ned by incubating 150 ~l of the Dembrane ~uspension with the radioligand (0.8 nM) in a ~inal volume of 1 ~l for 30 minutes at 25-C, in the absence or presence of the compound under 6tudy. Incubation takes place in the presence of 0.1 ~M paroxetine ~nd 1 ~M ketanserin. Non-specific binding i~ determined in the presence of 1 ~M ondansetron. After incubation, the test mixture is diluted with 5 ~l of ice-cold 50 mM
Tri6-HCl buffer (pH 7.4 8t 0 ' C) . The membranes are collected by filtration on Whatman GF/B~ filters pretreated with 0.05% of polyethylenimine, and washed with three volumes of 5 ml of ice-cold 50 mM Tris-HCl buffer.
The radioactivity retained on the filters is ~easured by liguid ~cintillation ~pectrometry at an efficiency of 50 to 60%.
The re6ultE are ~xpressed ~s the concentration (IC5o) of the compound under study which inhibits 50% of the binding of t~H]guip~zine, deter~ined by ~ graphic or ~athematical method. The compoundc of the invention which ~re ~o~t active in this test are characterized by I~o v~lues kelow 1 nM ~lO ~M)~
~ he r~ults of the ~iological te~ts show that the compounds of the inv~ntion are ligands for types - . .
. . ,., . , .
..
. . .
210706~
5-HT3 and 5-HT~ serotoninergic receptors.
They ~ay hence be used for the treatment and prevention of d~orders in which 5-HT3 ~nd 5-HT~
receptors are lnvolved, ~uch as nausea and ~omit$ng, S for xa~ple following antitumour treatment or the administration of ~n ~naeqthetic; disorders of the central nervous ~y~tem ~uch a6 schizophrenia, mania, anxiety ~nd depression: di~orders of cognition such ~s senile dementia or Alzheimer's presenile dementia;
dyskine~ia, pain, migraine and headache; disorders ~ssociated with alcohol or drug dependence or withdrawal; disorders of gastro intestinal function such ~s dyspepsia, peptic ulcer, heartburn, ~latulence:
disorders of the cardiovascular system and respiratory disorders.
They may also be used for the treatment and prevention of disorders 6uch as diarrhoea, irritable colon, oesophageal reflux, inte tinal motor disorders, disorderc of intestinal secretion, cystic fibrosic of the pancreas, carcinoid ~yndrome ~nd $ncontinence.
For thi~ purpo~e, they ~ay be presented in ~11 form6 ~uitable for oral or parenteral admini~tration, 6uch as tablet6, dragees, capsules including hard gel~tin capsules, ~uspensions or olution~ to be swallowed or injected, and the like, in combin~tion with suitable excipients, ~nd in doses that enable 0.005 to 10 ~g to be administQred 1 to 4 time6 a day.
- . . . .
: . . .. . .
Claims (6)
1. A compound which is a piperidine derivative of formula (I) (I) in which R represents hydrogen, or unbranched or branched C1-C6 alkyl; and Ar represents phenyl optionally substituted with one or more radicals selected from the halogens, amino, C1-C2 alkoxy and (C3-C6)cycloalkyl(C1-C2)alkoxy, or a heteroaryl group;
or a pharmaceutically acceptable acid addition salt thereof;
provided that when R is hydrogen Ar is not phenyl or 4-chlorophenyl.
or a pharmaceutically acceptable acid addition salt thereof;
provided that when R is hydrogen Ar is not phenyl or 4-chlorophenyl.
2. A compound according to claim 1, wherein Ar represents phenyl optionally substituted with one or more radicals selected from chlorine, amino, methoxy and cyclopropylmethoxy; imidazo[1,2-a]pyridin-2-yl;
3-indolyl; or 3-indazolyl optionally substituted at position 1 with a radical selected from C1-C2 alkyl and aryl(C1-C2)alkyl and at position 5 with a radical selected fron hydrogen, the halogens and (C1-C2)alkyl.
3. A process for preparing a compound as claimed in claim 1 or 2, which process comprises reacting a compound of formula (II) (II) in which Ar is as defined in claim 1 or 2 and X
represents a halogen or hydroxyl, with a piperidine derivative of formula (III) (III) in which R is as defined in claim 1 or 2, and optionally converting the piperidine derivative of formula (I) thereby produced into a pharmaceutically acceptable acid addition salt.
3. A process for preparing a compound as claimed in claim 1 or 2, which process comprises reacting a compound of formula (II) (II) in which Ar is as defined in claim 1 or 2 and X
represents a halogen or hydroxyl, with a piperidine derivative of formula (III) (III) in which R is as defined in claim 1 or 2, and optionally converting the piperidine derivative of formula (I) thereby produced into a pharmaceutically acceptable acid addition salt.
4. A compound according to claim 1 or 2 for use as a ligand for type 5-HT3 or 5-HT4 serotoninergic receptor.
5. A compound according to claim 4 for use in treating or preventing nausea, vomiting, a disorder of the central nervous system, a disorder of cognition, dyskinesia, pain, migraine, headache, a disorder associated with alcohol or drug dependence or withdrawal, a disorder of gastrointestinal function, a cardiovascular disorder, a respiratory disorder, diarrhoea, irritable colon, oesophogeal reflux, an intestinal motor disorder, a disorder of intestinal secretion, cystic fibrosis of the pancreas, carcinoid syndrome or incontinence.
6. A pharmaceutical composition comprising a compound as claimed in claim 1 or 2 and a pharmaceutically acceptable excipient.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9211551 | 1992-09-28 | ||
| FR9211551A FR2696177B1 (en) | 1992-09-28 | 1992-09-28 | Piperidine derivatives, their preparation and their therapeutic application. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2107061A1 true CA2107061A1 (en) | 1994-03-29 |
Family
ID=9433967
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002107061A Abandoned CA2107061A1 (en) | 1992-09-28 | 1993-09-27 | Piperidine derivatives, their preparation and their application in therapy |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US5434169A (en) |
| EP (1) | EP0591027A1 (en) |
| JP (1) | JPH06211838A (en) |
| KR (1) | KR940007020A (en) |
| CN (1) | CN1087339A (en) |
| AP (1) | AP424A (en) |
| AU (1) | AU658533B2 (en) |
| CA (1) | CA2107061A1 (en) |
| CZ (1) | CZ282080B6 (en) |
| DZ (1) | DZ1718A1 (en) |
| FI (1) | FI934221A (en) |
| FR (1) | FR2696177B1 (en) |
| HU (2) | HUT65303A (en) |
| IL (1) | IL107133A (en) |
| MA (1) | MA22981A1 (en) |
| MX (1) | MX9305932A (en) |
| NO (1) | NO933435L (en) |
| NZ (1) | NZ248776A (en) |
| OA (1) | OA09840A (en) |
| PL (1) | PL172860B1 (en) |
| SK (1) | SK103193A3 (en) |
| TN (1) | TNSN93107A1 (en) |
| TW (1) | TW272190B (en) |
| ZA (1) | ZA937156B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2191106T3 (en) * | 1995-09-18 | 2003-09-01 | Glaxo Group Ltd | USE OF ONDANSETRON IN THE MANUFACTURE OF A MEDICINAL PRODUCT FOR THE TREATMENT OF THE TEMBLOR. |
| EP0918518A4 (en) * | 1996-04-19 | 2002-05-02 | Univ California | Treatment of mood/affective disorders by glutamatergic upmodulators |
| FR2765221B1 (en) * | 1997-06-25 | 1999-07-30 | Synthelabo | DERIVATIVES OF 4 - [(1H-IMIDAZOL-4-YL) PIPERIDIN-1-YL] ANILIDE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| US6013654A (en) * | 1997-08-14 | 2000-01-11 | Pharmacia & Upjohn Company | Imidazo[1,2-A]pyridines for the treatment of CNS and cardiac diseases |
| GB9918425D0 (en) * | 1999-08-04 | 1999-10-06 | Novartis Ag | Organic compounds |
| US6887870B1 (en) * | 1999-10-12 | 2005-05-03 | Bristol-Myers Squibb Company | Heterocyclic sodium/proton exchange inhibitors and method |
| US7183305B2 (en) | 2003-11-11 | 2007-02-27 | Allergan, Inc. | Process for the synthesis of imidazoles |
| US7880017B2 (en) | 2003-11-11 | 2011-02-01 | Allergan, Inc. | Process for the synthesis of imidazoles |
| CA2616937A1 (en) * | 2005-07-29 | 2007-02-08 | F. Hoffman-La Roche Ag | Indol-3-yl-carbonyl-piperidin and piperazin derivatives |
| FR2925902B1 (en) * | 2008-01-02 | 2011-01-07 | Sanofi Aventis | IMIDAZO-1,2-α-PYRIDINE-2-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE |
| EP2379524A1 (en) | 2008-12-18 | 2011-10-26 | Boehringer Ingelheim International GmbH | Serotonin 5-ht2b receptor inhibitors |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61210080A (en) * | 1985-03-13 | 1986-09-18 | Chisso Corp | Production of aldehyde lactone |
| FR2579596B1 (en) * | 1985-03-26 | 1987-11-20 | Inst Nat Sante Rech Med | (IMIDAZOLYL-4) PIPERIDINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| US5008390A (en) * | 1985-05-23 | 1991-04-16 | Smithkline Beckman Corporation | Compounds for preparing 6-phenyl-2,3-dihydroimidazo[2,1-b]-thiazoles and corresponding thiazines |
| IT1230703B (en) * | 1989-01-26 | 1991-10-29 | Luso Farmaco Inst | IMIDAZOLONIC DERIVATIVES WITH ANTI-HYPERTENSIVE ACTIVITY, THEIR PREPARATION METHODS AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. |
| US4925851A (en) * | 1989-05-23 | 1990-05-15 | Sandoz Pharmaceuticals Corp. | 2- or 4-substituted-[2-(1H-imidazol-1-yl)ethyl]piperidines |
| FR2671083B1 (en) * | 1990-12-31 | 1994-12-23 | Inst Nat Sante Rech Med | NEWS 4- (4-IMIDAZOLYL) PIPERIDINES SUBSTITUTED IN 1, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATIONS. |
-
1992
- 1992-09-28 FR FR9211551A patent/FR2696177B1/en not_active Expired - Fee Related
-
1993
- 1993-09-17 TW TW082107634A patent/TW272190B/zh active
- 1993-09-20 EP EP93402281A patent/EP0591027A1/en not_active Ceased
- 1993-09-27 AU AU48606/93A patent/AU658533B2/en not_active Ceased
- 1993-09-27 FI FI934221A patent/FI934221A/en unknown
- 1993-09-27 JP JP5239571A patent/JPH06211838A/en active Pending
- 1993-09-27 KR KR1019930019850A patent/KR940007020A/en not_active Application Discontinuation
- 1993-09-27 ZA ZA937156A patent/ZA937156B/en unknown
- 1993-09-27 OA OA60417A patent/OA09840A/en unknown
- 1993-09-27 MA MA23294A patent/MA22981A1/en unknown
- 1993-09-27 AP APAP/P/1993/000575A patent/AP424A/en active
- 1993-09-27 CN CN93118082A patent/CN1087339A/en active Pending
- 1993-09-27 HU HU9302727A patent/HUT65303A/en unknown
- 1993-09-27 US US08/127,078 patent/US5434169A/en not_active Expired - Fee Related
- 1993-09-27 SK SK1031-93A patent/SK103193A3/en unknown
- 1993-09-27 NO NO933435A patent/NO933435L/en unknown
- 1993-09-27 CA CA002107061A patent/CA2107061A1/en not_active Abandoned
- 1993-09-27 NZ NZ248776A patent/NZ248776A/en unknown
- 1993-09-27 PL PL93300515A patent/PL172860B1/en unknown
- 1993-09-27 CZ CZ932015A patent/CZ282080B6/en unknown
- 1993-09-27 MX MX9305932A patent/MX9305932A/en unknown
- 1993-09-27 IL IL107133A patent/IL107133A/en not_active IP Right Cessation
- 1993-09-27 TN TNTNSN93107A patent/TNSN93107A1/en unknown
- 1993-09-28 DZ DZ930106A patent/DZ1718A1/en active
-
1995
- 1995-06-28 HU HU95P/P00490P patent/HU211249A9/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MA22981A1 (en) | 1994-04-01 |
| NO933435D0 (en) | 1993-09-27 |
| AP424A (en) | 1995-11-04 |
| CZ282080B6 (en) | 1997-05-14 |
| EP0591027A1 (en) | 1994-04-06 |
| TW272190B (en) | 1996-03-11 |
| CN1087339A (en) | 1994-06-01 |
| FR2696177B1 (en) | 1995-05-12 |
| CZ9302015A3 (en) | 1994-04-13 |
| NO933435L (en) | 1994-03-29 |
| AU4860693A (en) | 1994-04-14 |
| PL300515A1 (en) | 1994-04-05 |
| PL172860B1 (en) | 1997-12-31 |
| ZA937156B (en) | 1994-05-23 |
| DZ1718A1 (en) | 2002-02-17 |
| IL107133A0 (en) | 1993-12-28 |
| NZ248776A (en) | 1995-09-26 |
| TNSN93107A1 (en) | 1994-03-17 |
| MX9305932A (en) | 1994-04-29 |
| FI934221A (en) | 1994-03-29 |
| FI934221A0 (en) | 1993-09-27 |
| HU211249A9 (en) | 1995-11-28 |
| SK103193A3 (en) | 1994-08-10 |
| IL107133A (en) | 1998-03-10 |
| KR940007020A (en) | 1994-04-26 |
| JPH06211838A (en) | 1994-08-02 |
| FR2696177A1 (en) | 1994-04-01 |
| HU9302727D0 (en) | 1993-12-28 |
| US5434169A (en) | 1995-07-18 |
| OA09840A (en) | 1994-08-15 |
| HUT65303A (en) | 1994-05-02 |
| AP9300575A0 (en) | 1993-10-31 |
| AU658533B2 (en) | 1995-04-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2228370C (en) | Piperazino derivatives as neurokinin antagonists | |
| TW530048B (en) | New hydroxyindoles, their use as inhibitors of phosphodiesterase 4 and processes for their preparation | |
| AU646332B2 (en) | Piperidine derivatives, their preparation and their therapeutic application | |
| UA80567C2 (en) | The hydroxyindoles, their use as inhibitors of phosphodiesterase-4 and method for production thereof | |
| CZ61699A3 (en) | N-substituted indole-3-glyoxylamides exhibiting antiasthmatic, antiallergic amd immunosuppressive/immunomodulating activity | |
| JP4233322B2 (en) | Novel 7-azaindoles, their use as phosphodiesterase 4 inhibitors and methods for their preparation | |
| EA029097B1 (en) | Co-crystals and salts of ccr3-inhibitors | |
| KR101386354B1 (en) | 1,2-dihydro-2-oxoquinoline compounds as 5-ht₄ receptor ligands | |
| CA3083061A1 (en) | 1,2,4-oxadiazole derivatives as histone deacetylase 6 inhibitors | |
| CA2107061A1 (en) | Piperidine derivatives, their preparation and their application in therapy | |
| EP3700895B1 (en) | Polycyclic amides as muscarinic m1 receptor positive allosteric modulators | |
| JP2019520411A (en) | Inhibitor of tryptophan 2,3-dioxygenase | |
| CZ102896A3 (en) | 4-indolylpiperazinyl derivatives | |
| CA2317515A1 (en) | Oxazole derivatives as serotonin-1a receptor agonists | |
| CA3223322A1 (en) | Degrader compounds and uses thereof | |
| CA2889538A1 (en) | 1h-indole-3-carboxamide derivatives, and use thereof as p2y12 antagonists | |
| KR20060021830A (en) | 7-azaindoles and use thereof as therapeutic agents | |
| US6057340A (en) | Oxazole derivatives as serotonin-1A receptor agonists | |
| AU2006268527B2 (en) | Novel 1H-indole-pyridinecarboxamide and 1H-indole-piperidinecarboxamide derivatives and their use as hydroxylase tyrosine inducers | |
| HU201075B (en) | Process for producing 2-((piperidin-4-yl)-methyl)-benzofuro)2,3-c)- pyridine derivatives and pharmaceutical compositions containing them | |
| RU2032684C1 (en) | Method for preparing derivatives of 4-oxoquinoline or chroman or their pharmaceutically acceptable salts | |
| US20040019070A1 (en) | Pyrrole-condensed morphinoid derivatives | |
| KR20080025731A (en) | Substituted piperidine derivatives as somatostatin sst1 receptor antagonists | |
| RO110943B1 (en) | Derivates of indole-3,7-disubstitutes and preparation processes therefor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |